Major Risk Factors for Cardiovascular Disease: Title and subTitle BreakDebunking the "Only 50%" Myth

Conventional wisdom (or misconception) holds that the 4 major modifiable traditional cardiovascular risk factors—smoking, diabetes mellitus, hypertension, and hypercholesterolemia—account for "only 50%" of those who go on to develop coronary heart disease (CHD),^{1 - 2} even though the original source of this claim is not well documented. Thus, over the past decade, a search to discover novel markers and other nontraditional risk factors to assess cardiovascular risk has come to the forefront.

In 2 separate articles in this issue of THE JOURNAL, Khot et al³ and Greenland et al⁴ examined data from 14 randomized clinical trials (n = 122 458) and 3 observational studies (n = 386 915), respectively, and directly challenge this "only 50%" claim. The investigators report that 80% to 90% of patients who developed clinically significant CHD and more than 95% of patients who experienced a fatal CHD event in fact had at least 1 of these major cardiac risk factors. Remarkably, these findings perhaps underestimate the true extent of this phenomenon, especially given the self-report design of the observational studies and the fact that a number of patients were likely unaware of or not diagnosed as having risk factors at the time of evaluation.

In a third article in this issue of JAMA, Hackam and Anand⁵ summarize the evidence for emerging cardiovascular disease risk factors such as C-reactive protein, fibrinogen, lipoprotein(a), and homocysteine. The authors conclude that the current evidence is insufficient to conclusively support the additive value of these specific risk markers over conventional risk factors or global risk assessment strategies, such as the Framingham CHD risk stratification,^{6 - 7} currently in use.

Taken together, these 3 reports may have enormous public health implications for targeting a large segment of the population at risk of developing CHD. Smoking is arguably the single most important modifiable and preventable cardiovascular risk factor and one of the strongest independent predictors of premature CHD. In a recent meta-analysis of 20 clinical trials involving 12 603 patients, smoking cessation was associated with a 36% reduction in all-cause mortality among patients with CHD.⁸ Diabetes mellitus has been elevated to a level of CHD equivalent, primarily based on long-term epidemiological data that nondiabetic patients with prior myocardial infarction (MI) have a cardiac event rate similar to that of diabetic patients without prior MI.⁹

The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) demonstrated that in treatment of isolated hypertension (excluding high-risk groups in whom specific antihypertensive agents may have a demonstrated benefit, such as patients with prior MI, heart failure, diabetes, proteinuria, or other medical conditions), blood pressure control is of paramount importance.¹⁰ For the most part, primary cardiovascular outcomes were similar regardless of the agent used, and a multipharmacological approach (3 drugs on average) was frequently required. Two recent trials of cholesterol-lowering therapies have changed the focus to basing treatment on risk rather than low-density lipoprotein cholesterol (LDL-C) levels. The Heart Protection Study,¹¹ a secondary prevention trial involving patients with atherosclerotic vascular disease, diabetes, or both, demonstrated improved cardiovascular outcomes irrespective of the initial baseline LDL-C level. The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT),¹² a primary prevention trial of high-risk hypertensive patients (primarily older than 55 years) without evidence of CHD, demonstrated a 36% reduction in the combined primary end point of death and MI after only 3.3 years.

The 3 reports in this issue have a few important limitations. For example, the study by Khot et al did not have a control group. The investigation by Greenland et al, which used a broader definition of risk, found a high prevalence of at least 1 major risk factor in the general population without CHD. Although this study lacked specificity in predicting which patients with risk factors would develop CHD, it had a high negative predictive value (about 90%), suggesting that CHD events are unusual in the absence of these risk factors. The question nevertheless remains: Who will develop events among those with risk factors?

Furthermore, cardiac events were observed after a long period of follow-up (as long as 30 years), and the relevance of these findings to individual patients on a shorter-term basis remains unclear. Neither Khot et al³ nor Greenland et al⁴ reported whether these risk factors were treated or whether treatment was successful. Would better control of the cardiac risk factors have ameliorated CHD or CHD death? At what cost? Alternatively, can society afford not to aggressively screen and treat all patients at risk of coronary artery disease? Should clinicians treat cholesterol levels more aggressively and manage blood pressure beyond levels presently considered optimal? At what point should clinicians begin to treat individuals with hypertension or hypercholesterolemia for atherosclerotic vascular disease prior to clinical manifestations of the disease process?

Whereas primary and secondary prevention therapies address patient populations without and with documented CHD, respectively, "primordial" prevention (ie, involving overall lifestyle) is a relatively new concept that attempts to prevent the risk factors that may eventually lead to cardiovascular disease.¹³ In consideration of risk assessment for an individual patient, the relationship among these risk factors is synergistic. Thus, as the number of cardiac risk factors increases, a more aggressive approach to overall risk factor modification and treatment is needed. For example, national recommendations for blood pressure control and cholesterol control among patients with diabetes are significantly lower than levels that are considered acceptable for a general population.

In secondary prevention, patients with atherosclerotic vascular disease are at significantly increased risk of subsequent cardiac events. For example, compared with the risk in the general population, patients who have had MI have a 5- to 7-fold increased risk of recurrent MI.¹⁴ Furthermore, patients with cerebrovascular disease have a 2- to 3-fold increased risk of MI,¹⁵ and those with peripheral vascular disease have a 4-fold increased risk of MI.¹⁶ Thus, patients with clinically significant atherosclerosis warrant an aggressive approach to management of cardiovascular disease risk factors, given the high likelihood of developing further cardiovascular events.

Two recent reports have strongly suggested that C-reactive protein may add incremental information to the Framingham CHD risk score in predicting cardiovascular events and may identify a separate group of patients at risk of development of cardiovascular events from that due to LDL-C level.^{17 - 18} Several studies have addressed the use of C-reactive protein and other inflammatory markers in targeting the use of specific agents such as aspirin,^{19 - 20} 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins),²¹ clopidogrel loading dose prior to elective percutaneous coronary intervention,²² glycoprotein IIb/IIIa inhibitors,²³ and others. Ongoing randomized trials and observational studies are examining the role of C-reactive protein and other inflammatory markers in predicting cardiovascular risk over traditional methods currently in place and to ascertain the appropriateness of certain pharmacological therapies.

In the review by Hackam and Anand, the authors examined several emerging CHD risk factors but did not evaluate other markers of risk, such as LDL-C particle size and density, lipoprotein-associated phospholipase A₂, calcium scoring, carotid artery intimal-medial thickness, and brachial artery reactivity. But to date, none of these potential markers has conclusively added prognostic information beyond that of ascertaining the traditional risk factors and Framingham CHD risk stratification. In fact, a randomized trial by O'Malley et al²⁴ showed that using calcium scoring in an attempt to motivate patients to make evidence-based changes in risk factors did not result in modification of risk at 1 year.

Atherosclerosis is a systemic disease in need of a systemic solution, and a comprehensive approach involving risk factor modification and pharmacological treatment is needed for effective prevention of cardiovascular disease. Cornerstones of lifestyle modifications are well known and include smoking cessation, healthy diet (low saturated fat, low sodium), daily exercise (≥30 min/d), and weight management (to achieve a body mass index of less than 25). For patients with hypertension, blood pressure should be controlled to less than 140/90 mm Hg in the overall population and to 130/80 mm Hg in those with diabetes or renal disease.²⁵ Among patients with diabetes, tight control of blood glucose and hemoglobin A_1c levels is important. Pharmacological therapies have been shown to reduce cardiovascular morbidity and mortality. All patients with atherosclerotic vascular disease and diabetes should be strongly considered for aspirin,²⁶ statins,²⁷ and angiotensin-converting enzyme inhibitors,²⁸ irrespective of their baseline blood pressure, LDL-C level, or ejection fraction. In addition, β-blockers should be included for those with prior MI and symptomatic angina. Other patients who may have a significant 5- or 10-year risk of developing CHD should also be considered for aspirin²⁹ and statin therapies.²⁷

The 3 articles in the issue of THE JOURNAL provide evidence that convincingly challenges the frequent claim that "only 50%" of CHD is attributable to the conventional risk factors of smoking, diabetes, hypertension, and hyperlipidemia and clearly point out that additional research is needed to establish the role of other novel CHD risk markers. Perhaps more important, these studies emphasize that to reduce the burden of cardiovascular disease, physicians should have even greater vigilance in identifying conventional CHD risk factors and must redouble efforts to control them effectively.